Genetic Testing for Genetic Testing for Hereditary Cancer Hereditary Cancer SusceptibilitySusceptibility

The Ohio State UniversityThe Ohio State UniversityClinical Cancer Genetics ProgramClinical Cancer Genetics ProgramComprehensive Cancer CenterComprehensive Cancer Center

Learning ObjectivesLearning Objectives

The presentation will enable the participant to:The presentation will enable the participant to:

1. Explain the difference between hereditary 1. Explain the difference between hereditary and non-hereditary cancers.and non-hereditary cancers.

2. Point out the clinical characteristics of 2. Point out the clinical characteristics of hereditary cancer.hereditary cancer.

3. Summarize the importance of counseling 3. Summarize the importance of counseling prior to genetic testing for hereditary cancer.prior to genetic testing for hereditary cancer.

4. Identify the current benefits and limitations 4. Identify the current benefits and limitations of genetic testing for hereditary cancerof genetic testing for hereditary cancer

Most cancers are not inherited

5-10% hereditary

10-15% familial

75-85% sporadic

Who is at high risk for cancer?

History is the key…

CLUES:

Cancer in 2 or more close relatives (on same side of family)

Early age at diagnosis Bilateral/multiple cancers Multiple rare cancers Multiple primary tumors (breast and

ovary; colon and uterus) Evidence of autosomal dominant

transmission

CAUTION

Family History is Unreliable Many patients do not know the

details of their family history.– Specific sites of tumors unknown– Ages of onset unknown

Historical information needs to be verified in order to accurately assess risk.

Initial pedigree After review of records

Stomach Ca

Prostateproblem

s

Bone Cad. 48

Breast Ca

dx 45d. 48

Ovarian Cadx 43, d.

49

Prostate Cadx 50

Histories are dynamic

With the passage of time, additional diagnoses may have been made.

These changes may affect the likelihood of a hereditary cancer syndrome.

Initial History 2 years later

Colon Ca, 50Colon Ca, 50

Endometrial Ca, 44

Colon polyps, 48

Autosomal Dominant - Incomplete Penetrance

Penetrance is often incompletePenetrance is often incomplete May appear to “skip” generations May appear to “skip” generations Individuals inherit altered cancer susceptibilityIndividuals inherit altered cancer susceptibility gene, gene,

not cancernot cancer

NormaNormal l

Carrier, Carrier, affected with affected with cancercancer

Susceptible CarrierSusceptible Carrier

Sporadic Sporadic cancercancer

Genetic Counseling

Genetic Counseling:Purpose Appreciate the way heredity

contributes to cancer Understand an individual’s risk of

developing cancer Understand the options for dealing

with an increased risk for cancer Choose a course of action for

managing cancer risk that seems personally appropriate (genetic testing, screening or long-term follow up)

Genetic Counseling:What happens Collection of personal and family

history (3 generation pedigree) Education and risk assessment Options for genetic testing and

medical management– Discussion of risks, benefits and limitations– Screening/Chemoprevention/Prophylaxis

Follow-up– Provide psychosocial support– Family members

Breast Cancer

Breast cancer is common

1 in every 8 American women will be diagnosed with breast cancer in her lifetime

Misconceptions

Cancer on the father’s side of the family doesn’t count– Half of all women with hereditary risk

inherited it from their father Ovarian cancer is not a factor in breast

cancer risk– Ovarian cancer is an important indicator of Ovarian cancer is an important indicator of

hereditary risk, although it is not always hereditary risk, although it is not always presentpresent

The most important thing in the family history is the number of women with breast cancer– Age of onsetAge of onset of breast cancer is more of breast cancer is more

important than the number of women with the important than the number of women with the diseasedisease

Causes of Hereditary Breast Cancer

GeneGene

BRCA1BRCA1

BRCA2BRCA2

TP53 (Li Fraumeni)TP53 (Li Fraumeni)

PTEN (Cowden)PTEN (Cowden)

Undiscovered genesUndiscovered genes

Contribution to Contribution to Hereditary Breast Hereditary Breast

CancerCancer

20%–40%20%–40%

10%–30%10%–30%

<1%<1%

<1%<1%

30%–70%30%–70%

The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) Multiple cases of early onset breast Multiple cases of early onset breast

cancercancer Ovarian cancer Ovarian cancer Breast and ovarian cancer in the Breast and ovarian cancer in the

same womansame woman Bilateral breast cancerBilateral breast cancer Male breast cancer Male breast cancer Ashkenazi Jewish heritage Ashkenazi Jewish heritage

BRCA1-Associated Cancers: Risk by age 70

Possible increased risk of other cancers (e.g.,

prostate)

Breast cancer 50-85% (often early age at onset)

Second primary breast cancer 20%-60%

Ovarian cancer 15-45%

BRCA2-Associated Cancers: Risk by age 70

Increased risk of prostate, laryngeal, and pancreatic

cancers (magnitude unknown)

breast cancer (50-85%)

ovarian cancer (10-20%)

male breast cancer (6%)

Breast, dx 40Breast, dx 40d. 43d. 43

Ovary, dx 45Ovary, dx 45d. 47d. 47

Prostate, dx 58Prostate, dx 58

Breast, dx 33Breast, dx 334242

BRCA-mutation positive family

Unaffected

Affected with cancer3838 3535

Mutation carrier

d. 83d. 83

Relevance of Ashkenazi Jewish descent

1 in 40 (2.5%) Ashkenazi Jews (males and females) carry a BRCA1 or BRCA2 mutation

The carrier rate in non-Jewish populations is 1/400 (0.25%)

3 mutations (2 in BRCA1 and 1 in BRCA2) account for 95% of HBOC

Likelihood of developing breast cancer:Likelihood of developing breast cancer:– Gail modelGail model– Claus modelClaus model

Likelihood of having a BRCA1 or 2 mutation Likelihood of having a BRCA1 or 2 mutation – Myriad risk tablesMyriad risk tables– BRCAPRO, Couch, Shattuck-EidensBRCAPRO, Couch, Shattuck-Eidens

Likelihood of other breast cancer syndrome Likelihood of other breast cancer syndrome (Cowden, Li Fraumeni)(Cowden, Li Fraumeni)– Pedigree analysisPedigree analysis

Breast/Ovarian Cancer Risk Breast/Ovarian Cancer Risk AssessmentAssessment

BRCA1/2 Mutation Prob in a Woman with Breast Ca <50

Any relative Any relative with with

Br Ca < 50?Br Ca < 50?

Any Any relative relative with Ov with Ov

Ca?Ca?

Proband Proband with with

Bilateral Br Bilateral Br or Ov Ca?or Ov Ca?

ProbabilitProbability (%)y (%)

88

2525

4444

5555

6262

8181

Possible Results

Positive Negative

– True negative Negative result when family mutation

known Negative result in affected person

– Different gene? Can’t find mutation? Uninformative

– Negative in unaffected individual– Variant of uncertain significance

Additional information/testing needed

Important Important considerations when considerations when ordering testordering test Mutation detection rate?Mutation detection rate? Methods usedMethods used Frequency of variants of uncertain Frequency of variants of uncertain

significancesignificance– 10-12% in Caucasians and 40% in AA!10-12% in Caucasians and 40% in AA!

Testing technology always Testing technology always improvingimproving– Importance of ability to re-contact Importance of ability to re-contact

patientspatients

Breast Cancer: Surveillance Monthly BSE beginning at age 18Monthly BSE beginning at age 18 CBE every 6 months starting at age 25 CBE every 6 months starting at age 25

(or 5-10y before the earliest dx in family)(or 5-10y before the earliest dx in family) Annual mammography starting at age 25 Annual mammography starting at age 25

(or 5-10y before the earliest dx in family)(or 5-10y before the earliest dx in family) MRI now being used in conjunction with

mammogram; increased sensitivity but decreased specificity

Breast Cancer: Chemoprevention Matched case-control study

– 209 women with bilateral breast ca and BRCA1 or BRCA2 mutation

– 384 women with unilateral breast ca and BRCA1 or BRCA2 mutation

Tamoxifen protected against contralateral breast cancer– BRCA1 odds ratio 0.38 (95% CI 0.19–0.74)– BRCA2 odds ratio 0.63 (95% CI 0.20–1.50)

Narod Lancet 356:1876, 2000

Prophylactic Mastectomy

Total mastectomy is recommended method, if mastectomy is done.

Significantly reduces breast cancer risk in women with a family history (90%)

In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at 3 years follow-up

Hartman NEJM 340:77, 1999; Meijers-Heijboer NEJM 345: 1499, 2001

Ovarian Cancer: Surveillance

**NIH Consensus Conference, JAMA 273:491, 1995

“There are no data demonstrating that screening these high-risk women reduces their mortality from ovarian cancer. Nonetheless, [these measures] are recommended.”*

Pelvic examination and transvaginal ultrasound with color Doppler imaging every 6 months beginning at age 30-35 (or 5-10 years prior to the earliest dx in the family)

Concurrent serum CA-125

Ovarian Cancer: Chemoprevention

Limited data available for BRCA-mutation carriers; preliminary study showed a 60% risk reduction with ≥6 years use

Increases breast cancer risk in carriers by 1.2-1.4 fold

Oral Contraceptives

CASH study NEJM 316:650, 1987; Ursin Cancer Res 57:3678, 1997; Narod NEJM 339:424, 1998

40% to 50% risk reduction in general populationafter 3 years cumulative use

Prophylactic Oophorectomy Decreases risk of ovarian cancer by 95% (primary

peritoneal carcinoma may still occur)* Reduces risk of breast cancer by 63% if done

prior to age 40 and by 50% if done prior to age 50

Induces surgical menopause Laparoscopic procedure reduces postsurgical

morbidity Consider complete hysterectomy for

management of menopause – unopposed, low-dose estrogen

Rebbeck NEJM 346(21):1660, 2002; Kauf NEJM 346(21):1660, 2002

* 5-10% of carriers will have occult malignancy at time of PO - many in the fallopian tube

Benefits and Limitations of BRCA Testing

Benefits • Identifies high-risk

individuals

• Identifies noncarriers in families with a known mutation

• Allows early detection and prevention strategies

• May relieve anxiety

Risks and Limitations• Does not detect all

mutations

• Continued risk of sporadic cancer (those who test neg may have false sense of assurance)

• Efficacy of interventions unproven

• May result in psychosocial or economic harm

Case 1: RuthCase 1: RuthRuth is a 45 year old woman recently diagnosed Ruth is a 45 year old woman recently diagnosed with breast cancer and is concerned about the with breast cancer and is concerned about the risk to her daughters, ages 18 and 22. You risk to her daughters, ages 18 and 22. You inquire about family health history and find out inquire about family health history and find out the following information:the following information:

– Maternal family history is negative for cancerMaternal family history is negative for cancer

– Paternal family history is significant for:Paternal family history is significant for: Paternal aunt with ovarian cancer age at 55Paternal aunt with ovarian cancer age at 55 Paternal grandmother with breast cancer Paternal grandmother with breast cancer

age 42age 42

Case 1: PedigreeCase 1: Pedigree

Key

-Breast CA

-Ovarian CA

Dx 55d. 56

Dx 4282 yrs

Ruth45

English/Irish German

37 28

60 58

1822

Case 1: BRCA1/2 RisksCase 1: BRCA1/2 Risks

Risk of BRCA1/2 mutation: Risk of BRCA1/2 mutation:

– 36-44% risk of mutation in patient 36-44% risk of mutation in patient

Referral for Cancer Genetic Counseling is appropriate

– For cancer risk assessment and For cancer risk assessment and discussion of genetic testing for discussion of genetic testing for BRCA1/2BRCA1/2

Case 1: PedigreeCase 1: Pedigree

Key

-Breast CA

-Ovarian CA

Dx 55d. 56

Dx 4282 yrs

Ruth45

English/Irish German

60 58

1822

BRCA1 2800delAA

42 35

50% risk to daughters50% risk to daughtersBoth negative for specific mutation

BRCA1 +ive

BRCA1 +ive

s/p TAH/BSO

Case 1: Impact of results Case 1: Impact of results – medical management– medical management

Ruth Ruth – may want to consider oophorectomymay want to consider oophorectomy

Ruth’s daughters Ruth’s daughters – General pop’n risk for breast and ovarian General pop’n risk for breast and ovarian

cancer –follow ACS guidelinescancer –follow ACS guidelines– Cannot pass this on to their childrenCannot pass this on to their children

Ruth’s sister Ruth’s sister – Consider increased breast cancer screening +/- Consider increased breast cancer screening +/-

chemoprevention OR mastectomy/MRI and chemoprevention OR mastectomy/MRI and ovarian cancer screening and oophorectomy ovarian cancer screening and oophorectomy (after child-bearing, ~40)(after child-bearing, ~40)

Ruth’s 1Ruth’s 1stst cousin cousin– Consider increased breast cancer screening +/- Consider increased breast cancer screening +/-

chemoprevention or mastectomy/MRIchemoprevention or mastectomy/MRI

Case 1: Impact of results Case 1: Impact of results - psychosocial- psychosocial

Ruth feels relieved about daughters Ruth feels relieved about daughters but overwhelmed about risk of ovarian but overwhelmed about risk of ovarian cancercancer– timingtiming

Ruth’s daughters are happyRuth’s daughters are happy Ruth’s sister feels empowered by Ruth’s sister feels empowered by

informationinformation Ruth’s other sister wants nothing to do Ruth’s other sister wants nothing to do

with this and won’t go to the doctorwith this and won’t go to the doctor

Case 1: Take Home Case 1: Take Home MessagesMessages Risk assessment and genetic testing gives Risk assessment and genetic testing gives

information to patient AND family membersinformation to patient AND family members– Some family members may want this Some family members may want this

information and some may notinformation and some may not Genetic testing, when informative, can help Genetic testing, when informative, can help

individuals make decisions about early individuals make decisions about early detection and risk-reductiondetection and risk-reduction

Can also relieve anxiety about cancer risk Can also relieve anxiety about cancer risk (if negative)(if negative)

Informed decision-making imperativeInformed decision-making imperative Follow-up support and/or counseling Follow-up support and/or counseling

sometimes necessarysometimes necessary

Case 2: AlisonCase 2: Alison

Alison is a 40 year old daughter of one of your Alison is a 40 year old daughter of one of your patients. While attending her mother’s patients. While attending her mother’s appointment, she asks you for information about appointment, she asks you for information about the “breast cancer gene test”. She states she the “breast cancer gene test”. She states she wants this test.wants this test.

You ask her about her family historyYou ask her about her family history: :

– Mother with breast cancer - age 58Mother with breast cancer - age 58– Maternal aunt with breast cancer – age 65Maternal aunt with breast cancer – age 65– Paternal grandmother with breast cancer – age Paternal grandmother with breast cancer – age

7979

She feels that with her family history, breast She feels that with her family history, breast cancer is inevitable cancer is inevitable

Case 2: PedigreeCase 2: Pedigree

Dx 5865 yr

Dx 6571 yr

Dx 79d.81

Caucasian mix

Swedish / Finnish

Key:

-Breast CAAlison40 yr

15 yr

Menses began at age 11 1st child at age 25

No other risk factors

Case 2: Risk Assessment Case 2: Risk Assessment

Gail Model: Gail Model: – 5 year risk of breast cancer 1.2%; Lifetime risk of 5 year risk of breast cancer 1.2%; Lifetime risk of

20.4%20.4% Claus Model: Claus Model:

– Lifetime risk for breast cancer of 18.8% Lifetime risk for breast cancer of 18.8% Myriad table: Myriad table:

– 3.4% risk of BRCA1/2 mutation using family 3.4% risk of BRCA1/2 mutation using family historyhistory

Pedigree analysis: Pedigree analysis: – no indications of other breast cancer syndromesno indications of other breast cancer syndromes

Patient concernsPatient concerns

““Moderate/Familial” Moderate/Familial” RiskRisk

Clustering of cancer cases seen in the familyClustering of cancer cases seen in the family

Ages of onset not strikingly youngAges of onset not strikingly young

Risks for first degree relatives increasedRisks for first degree relatives increased

– Risk depends on number of family members Risk depends on number of family members affected, how closely related, ages of onsetaffected, how closely related, ages of onset

Multiple low-penetrance genes may play a Multiple low-penetrance genes may play a role and interact with environmental triggersrole and interact with environmental triggers

Case 2: PedigreeCase 2: Pedigree

Dx 5865 yr

Dx 6571 yr

Dx 79d.81

Caucasian mix

Swedish / Finnish

Key:

-Breast CAAlison40 yr

15 yr

Case 2: AssessmentCase 2: Assessment

Patient is in “Moderate/Familial” risk Patient is in “Moderate/Familial” risk categorycategory

Can begin breast cancer screening by age Can begin breast cancer screening by age 3535

Ovarian cancer risk not increasedOvarian cancer risk not increased Counseling issues:Counseling issues:

– Low risk for Low risk for BRCA1BRCA1 or or BRCA2BRCA2 mutation mutation – Screening and preventive strategies Screening and preventive strategies – Psychosocial – perceived risk, fearsPsychosocial – perceived risk, fears– Future research?Future research?

Case 2: Take Home Case 2: Take Home MessagesMessages Number of cancers in family is not as Number of cancers in family is not as

important as the important as the ages at diagnosisages at diagnosis– Side of family matters as well (all on one Side of family matters as well (all on one

side or some on each)side or some on each) Perceived risk does not always equal Perceived risk does not always equal

actual riskactual risk– Genetic counseling/risk assessment can Genetic counseling/risk assessment can

help help Genetic counseling/risk assessment Genetic counseling/risk assessment

does not always lead to genetic testingdoes not always lead to genetic testing

Case 3 - VeraCase 3 - Vera

Vera is a 38 year old Vera is a 38 year old microbiologist concerned about microbiologist concerned about her breast cancer riskher breast cancer risk

Family history of breast and Family history of breast and ovarian cancer in 2ovarian cancer in 2ndnd and 3 and 3rdrd degree relativesdegree relatives

Wants gene testingWants gene testing

Case 3 - PedigreeCase 3 - Pedigree

dx 55

dx 31 R brcadx 50 L brcad. 75 CVA

Vera38

6258

dx 55 colon or ovarian cad. 56

ItalianItalian

] [64

7

Menses began at age 12 1st child at age 31

No other risk factors

Case 3 - AssessmentCase 3 - Assessment

Gail risk = 14.3%Gail risk = 14.3% Claus = General population Claus = General population a prioria priori risk of mutation in Vera = risk of mutation in Vera =

3.75-16% (1.25-7%)3.75-16% (1.25-7%) a prioria priori risk of mutation in Vera’s risk of mutation in Vera’s

aunt = 15-64% (5-28%)aunt = 15-64% (5-28%) Recommended genetic testing for Recommended genetic testing for

Vera’s auntVera’s aunt

Case 3 – Counseling Case 3 – Counseling issuesissues Vera did not feel comfortable Vera did not feel comfortable

contacting her auntcontacting her aunt Vera wanted to be tested herselfVera wanted to be tested herself

– Genetic counseling covered risks, benefits Genetic counseling covered risks, benefits and and limitationslimitations of testingof testing

– Always try to start testing with an affected Always try to start testing with an affected individualindividual

Inconclusive resultInconclusive result– Negative in Vera – not true negativeNegative in Vera – not true negative– Variant of uncertain significanceVariant of uncertain significance

Case 3 – Test resultsCase 3 – Test results

dx 55

dx 31 R brcadx 50 L brcad. 75 CVA

Vera38

6258

dx 55 colon or ovarian cad. 56

ItalianItalian

] [65

7

+ BRCA2 N517S+ BRCA2 N517S

Variant of uncertain Variant of uncertain significancesignificance

Variants of uncertain Variants of uncertain significance (VUS)significance (VUS) 10-12% of people tested for 10-12% of people tested for BRCA1/2BRCA1/2

will have a VUSwill have a VUS Use lab data to determine significanceUse lab data to determine significance

– incidence in controlsincidence in controls– amino acid change and position in geneamino acid change and position in gene– segregation in family – free testing for VUS segregation in family – free testing for VUS

in certain family membersin certain family members– FUNCTIONAL STUDIESFUNCTIONAL STUDIES

On research basis onlyOn research basis only

Most are NOT disease causing but can Most are NOT disease causing but can take years to determine thistake years to determine this

Case 3 - Test resultsCase 3 - Test results

dx 55

dx 31 R brcadx 50 L brcad. 75 CVA

Vera38

6258

dx 55 colon or ovarian cad. 56

ItalianItalian

] [65

7

+ BRCA2 N517S+ BRCA2 N517S

+ BRCA2 N517S+ BRCA2 N517S

N517S is true mutationN517S is true mutationN517S is not true mutationN517S is not true mutation(1 in 4 chance of sharing by chance)(1 in 4 chance of sharing by chance)

Follow Vera as high risk Follow Vera as high risk until proven otherwiseuntil proven otherwise

Case 3 - Test resultsCase 3 - Test results

Decides toDecides tohave comprehensivehave comprehensiveBRCA1/2 testingBRCA1/2 testing

dx 55

dx 31 R brcadx 50 L brcad. 75 CVA

Vera38

6258

dx 55 colon or ovarian cad. 56

ItalianItalian

] [65

7

+ BRCA2 N517S+ BRCA2 N517S

+ BRCA1 C61G+ BRCA1 C61G

True Negative!True Negative!

+ BRCA2 N517S+ BRCA2 N517S

Follow ACS guidelinesFollow ACS guidelines

Take Home Messages – Take Home Messages – Case 3Case 3 Always try to start testing with an Always try to start testing with an

affected individualaffected individual Some patients have higher risk of Some patients have higher risk of

VUS than a true mutationVUS than a true mutation Pre-test counseling for VUS Pre-test counseling for VUS

importantimportant Don’t assume other family members Don’t assume other family members

won’t be interested in testingwon’t be interested in testing

Summary

When Should Genetic Testing Be Considered?

Significant family cancer history Reasonable likelihood of carrying a

mutation (affected usually tested first)

Results will influence medical management

Patient wants information (empowerment)

Genetic testing should always be performed in the context of genetic counseling– Discuss all medical and social concerns– Provide psychosocial support

It is easier to review the implications of testing prior to obtaining results

When Should Genetic Testing Be Considered?

Pros and Cons of Genetic Testing

Pros:

Improved cancer risk management

Information for individual and family members

Lifestyle decision making

Cons:

Limited testing is available, especially for moderate risk families

Results indicate probability, not certainty

Insurance issues, confidentiality

Insurance issuesInsurance issues

HIPAA protects patients with group HIPAA protects patients with group health insurance from genetic health insurance from genetic discriminationdiscrimination– Some gapsSome gaps

GINA –Passed the House; Senate GINA –Passed the House; Senate vote pendingvote pending– Cover gaps in HIPAACover gaps in HIPAA

Most states have state laws in Most states have state laws in placeplace– Wide variability in coverageWide variability in coveragehttp://www.genome.gov/10002077

http://www.cancerdiagnosis.nci.nih.gov/specimens/50_state_survey/appendix_a.htmhttp://www.cancerdiagnosis.nci.nih.gov/specimens/50_state_survey/appendix_a.htm

Implicationsfor the Entire Family

Consider the impact of testing on all family members.

Ultimately, testing is the individual’s choice.